Dennis Paul

A possible role for nerve growth factor in the augmentation of sodium channels in models of chronic pain

Inflammation induces an upregulation of sodium channels in sensory neurons. This most likely occurs as a result of the retrograde transport of cytochemical mediators released during the inflammatory response. The purpose of this study was to determine the effect of the subcutaneous administration of one such mediator, nerve growth factor (NGF), on the production of sodium channels in neurons of the rat dorsal root ganglion. For this, hindpaw withdrawal from either a thermal or mechanical stimulus was measured in rats at selected intervals for up to 2 weeks following injections of NGF. Sodium channel augmentation was then examined in dorsal root ganglia using site-specific, anti-sodium channel antibodies. Both thermal and mechanical allodynia was observed between 3 and 12 h post-injection. The hyperalgesic response returned to baseline by approximately 24 h post-injection. Sodium channel labeling was found to increase dramatically in the small neurons of the associated dorsal root ganglia beginning at 23 h, reached maximum intensity by 1 week, and persisted for up to 3 months post-injection. Pre-blocking NGF with anti-NGF prevented the NGF-induced decrease in paw withdrawal latencies and significantly reduced the intensity of sodium channel labeling. The results indicate that NGF is an important mediator both in the development of acute hyperalgesia and in the stimulation of sodium channel production in dorsal root ganglia during inflammation.

Ranolazine Attenuates Behavioral Signs of Neuropathic Pain

Ranolazine modulates the cardiac voltage-gated sodium channel (NaV 1.5) and is approved by the FDA in the treatment of ischemic heart disease. Ranolazine also targets neuronal (NaV 1.7, 1.8) isoforms that are implicated in neuropathic pain. Therefore, we determined the analgesic efficacy of ranolazine in a preclinical animal model of neuropathic pain. Both intraperitoneal and oral administration of ranolazine dose-dependently inhibited the mechanical and cold allodynia associated with spared nerve injury, without producing ataxia or other behavioral side effects. These data warrant clinical investigation of the potential use of ranolazine in the treatment of neuropathic pain.

Analgesic effects of Tyr-W-MIF-1: a mixed μ2-opioid receptor agonistμ1-opioid receptor antagonist

Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH2) is a naturally occurring neuropeptide that displays high selectivity for mu-opioid receptors. Recently, intrathecal (i.t.) Tyr-W-MIF-1 was shown to induce potent analgesia mediated through spinal mu2-opioid receptors in mice. In the current study, we investigated the supraspinal analgesic effects of Tyr-W-MIF-1 using intracerebroventricular (i.c.v.) administration in mice. I.c.v. Tyr-W-MIF-1 induced a dose-dependent analgesic response with an ED50 of 31.4 micrograms that was antagonized by i.c.v. naloxone (ED50 = 4.46 nmol) and the mu-opioid receptor antagonist beta-funaltrexamine but not by the mu1-opioid receptor-selective antagonist naloxonazine. I.t. naloxone (ED50 = 0.12 nmol), however, was nearly 40-fold more potent than i.c.v. naloxone at antagonizing i.c.v. Tyr-W-MIF-1-induced analgesia. Tyr-W-MIF-1 also possesses antagonist activity at mu1-opioid receptors in brain. Coadministration of i.c.v. Tyr-W-MIF-1 with i.c.v. morphine or i.c.v. [D-Ala2, MePhe4, Gly(ol)5]enkephalin (DAMGO) significantly decreased the analgesic response to either drug administered alone. Thus, Tyr-W-MIF-1 functions as a mixed mu2-opioid receptor agonist/mu1-opioid receptor antagonist after i.c.v. administration in mice.

Intrathecal Tyr-W-MIF-1 produces potent, naloxone-reversible analgesia modulated by α2-adrenoceptors

Spinal administration of morphine or [D-Ala2,MePhe4,Gly(ol)5)]enkephalin (DAMGO) produces potent, naloxone-reversible analgesia that is modulated by alpha 2-adrenoceptors. Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH2) is a naturally occurring, amidated tetrapeptide that is structurally related to the melanocyte-stimulating hormone release inhibiting factor-1 (MIF-1) family of endogenous peptides. Tyr-W-MIF-1 displays high selectivity for the mu-opioid receptor. We investigated the effect of spinal administration of Tyr-W-MIF-1 on analgesia using the mouse tail-flick assay. Intrathecal (i.t.) administration of Tyr-W-MIF-1 produced a dose-dependent analgesic response, with an ED50 of 0.41 microgram, that was reversed by naloxone. Pretreatment with the mu-opioid receptor-selective antagonist beta-funaltrexamine blocked the effect of i.t. Tyr-W-MIF-1. However, pretreatment with the mu1-opioid receptor-selective antagonist naloxonazine did not antagonize the analgesia, indicating the effect was mediated through spinal mu2-opioid receptors. Pretreatment with desipramine, an inhibitor of norepinephrine reuptake, potentiated the analgesic effect of i.t. Tyr-W-MIF-1, producing a 3.1-fold leftward shift in the dose-response curve. Spinal administration of yohimbine, an alpha 2-adrenoceptor-selective antagonist, significantly attenuated the analgesic effect of Tyr-W-MIF-1. Thus, the potent analgesic effect of i.t. Tyr-W-MIF-1 is mediated through spinal mu2-receptors, and is modulated by norepinephrine and alpha 2-adrenoceptors.

Differential cross-tolerance between analgesia produced by α2-adrenoceptor agonists and receptor subtype selective opioid treatments

Analgesic cross-tolerance between alpha 2-adrenoceptor and opioid receptor agonists was studied using the mouse tail-flick assay. Mice tolerant to clonidine (0.3 mg/kg s.c.) or xylazine (7 mg/kg s.c.) were cross-tolerant to morphine (5 mg/kg s.c.), nalorphine (70 mg/kg s.c.) and supraspinal [D-Ala2,MePhe4,Gly(ol)5]enkephalin (DAMGO; 4 ng i.c.v.), but not trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)- cyclohexyl] benzeneacetamide methanesulfonate (U50,488; 5 mg/kg s.c.), spinal DAMGO (10 ng i.t.), supraspinal [D-Pen2,D-Pen5]enkephalin (DPDPE; 9 micrograms i.c.v.) or spinal DPDPE (700 ng i.t.). In the complimentary studies, mice tolerant to morphine and nalorphine were cross-tolerant to both of the alpha 2-adrenoceptor agonists, but U50,488 tolerant mice were not. The results suggest differential interactions between alpha 2-adrenoceptor and mu 1-, mu 2-, delta-, kappa 1- and kappa 3-opioid analgesic circuitry.

Ranolazine Attenuation of CFA-induced Mechanical Hyperalgesia

OBJECTIVE To determine whether ranolazine, a new anti-angina medication, could be an effective analgesic agent in complete Freunds adjuvant-induced inflammatory pain. BACKGROUND Plantar injection of complete Freunds adjuvant (CFA) produces an extended period of hyperalgesia that is associated with a dramatic up-regulation of Na(v) 1.7 sodium channels in populations of large and small dorsal root ganglion neurons related to the injection site. Ranolazine appears to produce its anti-angina effect through blocking the late sodium current associated with the voltage-gated sodium channel, Na(v) 1.5. Because ranolazine also inhibits Na(v) 1.7, and 1.8, we sought to determine whether it could be an effective analgesic agent in CFA-induced inflammatory pain. METHODS Baseline determinations of withdrawal from thermal and mechanical stimulation were made in Sprague-Dawley rats ( approximately 300-350 x g). Following determination of baseline, one hindpaw in each group was injected with 0.1 mL of CFA. The contralateral paw received saline. Thermal and mechanical stimulation was repeated on the third day post-injection. Vehicle (0.9% isotonic saline; pH 3.0) or ranolazine was then administered in randomized and blinded doses either by intraperitoneal (ip) injection (0, 10, 20, and 50 mg/kg) or by oral gavage (po; 0, 20, 50, 100, and 200 mg/kg). Animals were again tested 30 minutes (ip) and 1 hour (po) after drug administration. RESULTS Ranolazine produced dose-dependant analgesia on mechanical allodynia induced by CFA injection, but had no effect on thermal hyperalgesia. CONCLUSIONS Ranolazines potential as a new option for managing both angina and chronic inflammatory pain warrants further study.

Cross-tolerance between analgesia produced by xylazine and selective opioid receptor subtype treatments.

Opioid receptor agonists produce analgesia through multiple systems activated by stimulation of mu(1), mu(2), delta(1), delta(2) and kappa(1) opioid receptors. Morphine analgesia is modulated by stimulation of alpha(2) adrenoceptors. To understand how multiple opioid analgesic systems interact with alpha(2)-adrenoceptor systems, analgesic cross-tolerance between the alpha(2) adrenoceptor agonist xylazine and opioid receptor agonists was studied using the mouse tail-flick assay. Mice received either xylazine (20 mg/kg, s.c.) or saline (1 ml/kg) for five days. On day six, mice received a dose of s.c. xylazine, i.c.v. [D-Ala(2),MePhe(4),Gly(ol)(5)]enkephalin (DAMGO), i.t. Tyr-Pro-Trp-Gly-NH(2) (Tyr-W-MIF-1), i.c.v. or i.t. [D-Pen(2),D-Pen(5)]enkephalin (DPDPE), i.t. [D-Ala(2)]deltorphin II (deltorphin II), or s.c. trans-(+/-)-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl-cyclohexyl] benzeneacetamide (U50,488). Xylazine tolerant mice required 4. 57-fold more xylazine to elicit the same response as saline treated animals and showed a 2.55-fold shift in i.c.v. DAMGO and a 3.37-fold shift in i.c.v. DPDPE antinociception. No cross-tolerance was seen with i.c.v. deltorphin II, i.t.Tyr-W-MIF-1, i.t. DPDPE, i.t. Tyr-W-MIF-1 or s.c. U50,488. These results implicate alpha(2) adrenoceptor systems in the modulation of supraspinal mu(1), and delta(1) opioid analgesic circuitry and raise the possibility that mu(2), delta(2) or kappa(1) opioid receptor agonists may be alternated with alpha(2) adrenoceptor agonists to minimize tolerance or treat opioid-tolerant patients.

Oxidation Sensitive Nociception Involved in Endometriosis Associated Pain

Abstract Endometriosis is a disease characterized by the growth of endometrial tissue outside the uterus and is associated with chronic pelvic pain. Peritoneal fluid (PF) of women with endometriosis is a dynamic milieu and is rich in inflammatory markers, pain-inducing prostaglandins prostaglandin E2 and prostaglandin F2&agr;, and lipid peroxides; and the endometriotic tissue is innervated with nociceptors. Our clinical study showed that the abundance of oxidatively modified lipoproteins in the PF of women with endometriosis and the ability of antioxidant supplementation to alleviate endometriosis-associated pain. We hypothesized that oxidatively modified lipoproteins present in the PF are the major source of nociceptive molecules that play a key role in endometriosis-associated pain. In this study, PF obtained from women with endometriosis or control women were used for (1) the detection of lipoprotein-derived oxidation-sensitive pain molecules, (2) the ability of such molecules to induce nociception, and (3) the ability of antioxidants to suppress this nociception. LC–MS/MS showed the generation of eicosanoids by oxidized-lipoproteins to be similar to that seen in the PF. Oxidatively modified lipoproteins induced hypothermia (intracerebroventricular) in CD-1 mice and nociception in the Hargreaves paw withdrawal latency assay in Sprague-Dawley rats. Antioxidants, vitamin E and N-acetylcysteine, and the nonsteroidal anti-inflammatory drug indomethacin suppressed the pain-inducing ability of oxidatively modified lipoproteins. Treatment of human endometrial cells with oxidatively modified lipoproteins or PF from women with endometriosis showed upregulation of similar genes belonging to opioid and inflammatory pathways. Our finding that oxidatively modified lipoproteins can induce nociception has a broader impact not only on the treatment of endometriosis-associated pain but also on other diseases associated with chronic pain.

Medications of abuse in pain management

Purpose of review Chronic pain leads to a reduction in the quality of life for those who suffer it. Due also to high medical costs and lost productivity, chronic pain is a significant burden on society. One contributor to the burden of pain is the fear that medications used in pain management produce dependency, leading to diversion and addiction. Certain medications used in practice, although not abused by the patient, seem to be favored and these are frequently reported to be used recreationally by the nonpatient population. This report identifies medications that most frequently present a problem in pain practices, why they are a problem, and possible alternatives to their use. Recent findings Problem medications used in analgesic regimens tend to be those that have rapid onset due to their lipophilic nature or route of administration, short duration, and a sedating or energizing effect. These medications are generally more affordable than alternatives with less abuse potential. These medications are more often covered by insurance and more frequently prescribed. Changes in prescribing habits have resulted in predictable shifts in abuse. Summary Addiction and diversion of prescription medications is a multidimensional problem. Its multifactorial solution will require efforts at many regulatory levels.

Hydrocodone extended-release: Pharmacodynamics, pharmacokinetics and behavioral pharmacology of a controversy

Recently, the U.S. Food and Drug Administration (FDA) approved Zohydro(®), an extended release formulation of the opioid analgesic hydrocodone that contains no acetaminophen. This approval was against the recommendation of the FDAs Expert Panel. Subsequently, both chronic pain advocates and anti-drug abuse advocates have steadfastly expressed their support of, or astonishment at this decision. Here, we review the pharmacokinetics, pharmacodynamics, safety and abuse liability of this hydrocodone formulation and how it relates to the Expert Panels opinion and the FDA decision. We discuss the important issues, risk mitigation, potential use of abuse deterrents, and how the different viewpoints of the Expert Panel and FDA decision makers resulted in the approval and subsequent controversy.